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Heba Ahmed Osman,1 Hanaa Nafady-Hego,2 Khalid Ali Nasif,3,4 Heba A Ahmed,5 Ekram Abdel-Rahman Mahmoud,6 Noher Mohamad Abass,7 Amal Rayan,8 Marwa Ahmed Mahmoud,9 Asmaa Nafady10 1Department of Tropical Medicine and Gastroenterology, Qena Faculty of Medicine, South Valley University, Qena, Egypt; 2Department of Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt; 3Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, Kingdom of Saudi Arabia; 4Department of Biochemistry, Faculty of Medicine, Minia University, Minia, Egypt; 5Department of Clinical and Chemical Pathology Sohag Faculty of Medicine Sohag University, Sohag, Egypt; 6Department of Medical Microbiology & Immunology, Faculty of Medicine, Sohag University, Sohag, Egypt; 7Department of Internal Medicine, Faculty of Medicine, Sohag University, Sohag, Egypt; 8Department of Clinical Oncology, Faculty of Medicine, Assiut University, Assiut, Egypt; 9Department of Medical Physiology, Faculty of Medicine, Sohag University, Sohag, Egypt; 10Department of Clinical and Chemical Pathology, Qena Faculty of Medicine, South Valley University, Qena, EgyptCorrespondence: Heba Ahmed Osman, Tropical Medicine and Gastroenterology, Qena Faculty of Medicine, South Valley University, Qena, Egypt, Email drheba.saleh@med.svu.edu.eg; hebaahmed198098@yahoo.comIntroduction: HCC is frequently diagnosed late, when only palliative treatment is available. So, we try to use different immunological markers to identify early HCC in patients with unremarkable raised AFP.Methods: This study was conducted on 112 participants divided into two equal groups: Group I, 56 patients with liver cirrhosis and different stages of HCC; Group II, 56 patients with liver cirrhosis. The diagnosis of HCC was based on AASLD guidelines. TNM and BCLC classification systems are used for staging of HCC.Results: A significant reduction in the median percentage of lymphocyte subset (CD3+, CD4+, CD8+, CD19+) and NK cell percentage (CD56+) has been detected in HCC patients (all P < 0.001). In the HCC group the median monocyte subpopulations CD14+ CD16− Classical, CD14++ CD16+ Intermediate, and CD14−+ CD16++ Non-Classical were 11.7, 4.0, and 3.5, respectively, with marked reduction compared with liver cirrhosis group (all P < 0.001). Patients with advanced stages (BCLC C and D) were more likely to have significantly higher median CD33+ than patients with early stages (BCLC A and B) (P = 0.05); also, the median levels of HLA DR+ lymphocytes % in the HCC case group were 21.8 in patients with advanced disease (BCLC C and D) and 13.1 in patients with early stages of the disease (P = 0.04). Patients with late stage (TNM III) were more likely to have significantly higher median CD14+ CD16− Classical monocyte subset, CD36+ HLA DR+, and CD36+ CD16− than patients with early stages (TNM I and II).Conclusion: Patients with HCC with unremarkable raised AFP showed marked reduction in lymphocytes, natural killer cells, and all monocyte subpopulations. In addition, patients with advanced HCC showed increased CD33+ and HLA DR+ lymphocytes %, CD14+ CD16− Classical monocyte subset, CD36+ HLA DR+, and CD36+ CD16− compared with patients with early stages of HCC.Keywords: monocyte subpopulation, lymphocyte subset, hepatocellular carcinoma, Barcelona clinic liver cancer, tumor (T), nodes (N), metastases (M)